The overall aim of the proposed research is to examine aortic histamine metabolism in rats following induction of diabetes mellitus, in an attempt to gain insight into (1) intrinsic systems regulating large vessel transmural permeability and (2) reasons for well known increased susceptibility of diabetics to atherosclerosis. Underlying the entire scope of the proposed research are the assumptions that vascular injury is a primary causative factor in the pathogenesis of atherosclerosis, that such injury occurs in diabetics either through hyperglycemia, hyperlipidemia, hypoinsulinism, or through other components of the diabetic syndrome, that aortic transmural permeability is influenced by intrinsic aortic histamine synthesis and catabolism which alter physiologically active aortic histamine pools and that a very early component of the initial atherosclerotic lesion may in part represent a prolonged phase of inflammation mediated by increased histamine synthesis and/or decreased histamine catabolism. The specific aims of the proposed research may be summarized as follows. First, histamine synthesis, catabolism and the intracellular histamine content of endothelial cells and subjacent smooth muscle cells will be determined in rats having various degrees of diabetes for various time periods ranging from 2 weeks to 3 months. Next, experiments will be conducted to determine effects of insulin treatment on these parameters. Experiments will also be undertaken to evaluate aortic permeability to albumin and other macromolecules under these conditions and in relation to the above histamine parameters. Experiments will then be conducted in which effects of inhibition of histamine synthesis on aortic as well as endothelial cell and smooth muscle cell permeability will be examined in both untreated and insulin-treated diabetic rats. All alterations will be evaluated in relation to vascular wall integrity, as determined from both light and electron microscopic evaluations.